Identification of a novel multifunctional structural domain in the herpes simplex virus type 1 genome: implications for virus latency

This study identifies a novel regulatory domain within the herpes simplex virus type 1 (HSV-1) genome called RE1, consisting of 10 tandem copies of a CT-rich sequence located upstream of latency-associated transcripts (LATs). Using electrophoretic mobility shift assays, researchers demonstrated that this domain binds multiple host-cell nuclear proteins from rat brain and HeLa cell extracts. The RE1 element specifically interacts with three classes of factors: classical double-stranded DNA-binding proteins recognizing CT-rich sequences, single-stranded DNA-binding proteins, and nucleosomal remodeling proteins related to BGP1. The authors propose that RE1 functions as a multifunctional regulatory element that may act simultaneously as a transcriptional regulator and as a modulator of chromatin structure in the latent viral genome. This novel mechanism could influence both immediate early gene expression and LAT expression, potentially affecting the establishment, maintenance, and reactivation of HSV-1 latency. Similar regulatory motifs were identified in the related varicella-zoster virus, suggesting a conserved function across alphaherpesvirus latency mechanisms.

Key findings

• The RE1 domain in HSV-1 consists of 10 tandem CT-rich repeats that bind multiple classes of host nuclear proteins involved in transcriptional regulation and chromatin remodeling.
• RE1 sequences specifically bind single-stranded DNA-binding proteins like hnRNP K to individual DNA strands, potentially regulating transcription and DNA topology.
• The RE1 domain interacts with nucleosomal restructuring proteins (BGP1-related factors) that may remodel chromatin structure over the latency-associated transcript and immediate early gene regions.
• This multifunctional domain may simultaneously regulate transcription and alter DNA topology, representing a novel mechanism for controlling HSV-1 latency maintenance and reactivation.